This application for the mentored K08 award is submitted with the goal of providing the candidate with the further experience and training necessary to function as an independent investigator working in the field of autoimmunity and apoptosis. Systemic lupus erythematosus (SLE) is characterized by a unique spectrum of pathogenic autoantibodies, mainly directed at ubiquitous nuclear targets, namely the autoantigens. To understand the etiology of SLE, it is important to know how these specific autoantigens are driving the autoimmune response. The source of autoantigens and the reason why only certain nuclear and cytoplasmic proteins become autoantigens are still unknown. Because impaired clearance of apoptotic cells or their debris can lead to SLE-like disease in certain models and because SLE autoantigens concentrate on apoptotic blebs of cells injured by UV-B, apoptotic cells have been proposed as a critical reservoir of autoantigens that may play an essential role in spontaneous autoimmune disease. With this proposal the candidate intends to explore the possibility that autoantigens constitute a unique set of immunogens within the apoptotic cells by studying the biology of the autoantigen clustering into blebs and bodies during apoptosis and investigating its immunological relevance in both B cells and dendritic cells (DC). The proposal will provide important insights into the source of autoantigens, and into the role of apoptosis in exposing lupus antigens to the immune competent cells. The proposal may also lead to a better understanding of how autoimmunization in a lupus prone individual takes place and therefore to a rational therapy for targeting apoptotic cells and their products in SLE. Dr. Caricchio long-term goals are to apply and to extend the knowledge obtained with in vitro systems to lupus mouse models and ultimately to human lupus and to further investigate the role of apoptotic cells in the pathogenesis of SLE. Under Dr. Cohen's and other mentors' guidance, Dr. Caricchio plans during the period of the award to establish an independent laboratory and pursue his own supported projects. The Division of Rheumatology and in general the biomedical research community of the University of Pennsylvania will support his scientific growth both intellectually and as a bench researcher.